Field of the Invention
The present invention relates to a method for synthesis of anabaseine derivatives, especially to a method for synthesis of 4-OH substituted anabaseine derivative.
Descriptions of Related Art
Acetylcholine is a neurotransmitter released by nerve cells of central and peripheral nervous systems for intercommunication between the nervous system and the immune system. The nervous system sends signals through acetylcholine for inhibition of inflammatory processes. Acetylcholine works by binding to receptors located on surface of cells such as neurons or immune cells. There are two main classes of acetylcholine receptor, muscarinic (M) and nicotinic (N).
Nicotine can mimic the action of acetylcholine at acetylcholine receptors and bind to acetylcholine receptors as an agonist of the Alpha-7(α7) nicotinic acetylcholine receptor. Thus some research shows that nicotine is promising for the treatment of cranial nerve diseases such as Alzheimer's disease, Parkinson's disease, and Tourette syndrome. In some patients, their learning abilities are even recovered. Moreover, nicotine also activates α-7 nicotinic acetylcholine receptors on macrophages and suppresses release of pro-inflammatory cytokines. Thus nicotine acts as an anti-inflammatory agent in patients with ulcerative colitis, Kaposi's sarcoma epilepsy and asthma.
However, nicotine is highly toxic and addictive, and is associated with cardiovascular disease, cancer, etc. Thus nicotine is unable to be used as a drug due to its harmful effects. A series of drugs with similar structure of nicotine have been developed to provide pharmaceutical effects similar to nicotine without toxic effect. Anabaseine is a representative of these drugs.
Anabaseine is an Alpha-7 nicotinic acetylcholine receptor agonist and initially designed for treatment of Alzheimer's disease. It improves cognitive functions of the Alzheimer's patients, without poisoning and addiction of nicotine. In the research now, anabaseine is modified in order to enhance its pharmacological properties. 4-OH-anabesine has the most healing effect among the anabaseine derivatives.
Among the techniques available now, 4-OH-anabesine is synthesized by reflux of anabaseine and 4-hydroxyethoxy-2-methoxybenzaldehyde with catalysis of concentrated hydrochloric acid. The final product obtained is a 4-OH substituted anabaseine derivative named 3-[(4-Hydroxyethoxy-2-methoxy)-benzylidene]anabaseine. The anabaseine used is prepared by nucleophilic substitution reaction of δ-valerolactam with ethyl nicotinate. The intermediate product, lithium 3-nicotinoyl-2-piperidone enolate, is obtained. Then the intermediate product is heated under reflux with concentrated hydrochloric acid to get cyclized product-anabaseine. The cyclized product is filtered and washed with solvents.
Yet anabaseine is easy to dissolve in solvents such as water under normal temperature. Thus anabaseine is easy to be lost during the washing step and the yield is dropped to 20-30%. Moreover, TLC test and Proton Nuclear Magnetic Resonance (1H NMR) show that there are still some by-products after substitution of 4-OH group. Thus the elution time is quite long while using column chromatography for separation. The yield of column chromatography is only about 40%-50%, a bit insufficient. Thus there is room for improvement.